Amivantamab With Tyrosine Kinase Inhibitors (TKI) for Advanced NSCLC With ALK, ROS1, or RET Alterations

Inclusion Criteria:

1. Provision to sign and date the informed consent form.

2. Stated willingness to comply with all study procedures and be available for theduration of the study.

3. Participant is ≥ 18 years of age.

4. Participant has histologic or cytologic confirmation of locally advanced (unresectable) or metastatic NSCLC with a known (and documented) ALK, ROS1, or RETfusion based on approved diagnostic testing methods specified below. Not that NGStesting is required for all participants, but screening if any of the test below arepositive. a. IHC: For ALK NSCLC only using the ALK D5F3 antibody b. FISH with ≥15% of 100cells sampled constituting positivity c. NGS using a CLIA-certified test

5. Participants must have clinical progression on at least one prior FDA-approved TKI.They must be on a TKI at the same dose for at least 8 weeks without radiographicprogression or clinical intolerance of the TKI prior to enrolling on this study.TKIs that will be considered include (but not limited to):

6. ALK fusions - alectinib, brigatinib, lorlatinib

7. ROS1 fusions - entrectinib, lorlatinib

8. RET fusions - selpercatinib, pralsetinib

9. Participants must have at least 1 measurable lesion by RECIST v1.1 criteria usingcomputed tomography (CT) scan or magnetic resonance imaging (MRI).

10. Measurable CNS lesions ≥10mm must be captured as overall and intracranialRECIST target lesions. CNS lesions 5-9mm may be included in the intra-cranialdata set alone but must be listed as non-target lesions.

11. Measurable, treated brain metastases (≥ 10mm) growing after whole-brainradiotherapy (WBRT) or resection are allowed as target lesions, but lesionsgrowing after stereotactic radiosurgery (SRS) are allowed as target lesionsonly if radiation necrosis or pseudoprogression is ruled out.

12. Participant has an Eastern Cooperative Oncology Group (ECOG) score of 0-2

13. Participant has a life expectancy of greater than 12 weeks, per investigatordiscretion.

14. Participant can ingest oral medications.

15. Participant has received the final dose of any of the followingtreatments/procedures with the specified minimum intervals before the first dose ofstudy drug (unless in the opinion of the Sponsor-Investigator, the medication willnot interfere with the study or compromise participant safety). Chemotherapy 21 days Antibody-drug conjugate (ADC) 28 days Immune checkpointinhibitors (ICI) 28 days Locally ablative radiotherapy 28 days Palliativeradiotherapy 14 days Major surgery 28 days

16. Participant has adequate organ function as determined by the following laboratoryvalues. Absolute neutrophil count (ANC)* ≥ 1,500/mm3 (≥ 1.5 x One times ten to the ninth/L)Platelets† ≥ 75,000/mm3 (≥ 75 x One times ten to the ninth/L) Hemoglobin† ≥ 9 g/dLRenal function: Serum creatinine ≤ 1.5 x upper limit normal (ULN) OR creatinineclearance ≥50 mL/min/1.73 m2 via Cockcroft-Gault Liver transaminases (ALT/AST) ≤ 3 xULN

• 5 x ULN, if liver metastases are present on screening Bilirubin ≤ 1.5 x ULN

• 3.0 x ULN, if patient has Gilbert's disease Amylase and lipase ≤ 1.5 x ULN

• Participants cannot be receiving growth factor support usinggranulocyte-stimulating colony factor (G-CSF) during the screening visit.

• Participants cannot receive transfusion support up to one week priorto the screening period.

12. Female participant of childbearing potential (defined as a sexually mature woman whohas not undergone a hysterectomy [surgical removal of the uterus] or bilateraloophorectomy, or if ≥ 45 years old, has not been naturally postmenopausal for atleast 24 consecutive months [i.e., has had menses at any time during the preceding 24 consecutive months]) must:

13. Have 1 negative pregnancy test as verified by an Investigator prior to startingstudy therapy. This applies even if the subject practices true abstinence fromheterosexual contact.

14. Either commit to true abstinence from heterosexual contact (which must bereviewed on a monthly basis) or agree to use and be able to comply with abarrier method plus a hormonal method of contraception without interruption 28days prior to starting investigational product, during the study therapy (including dose interruptions), and for 3 months after discontinuation (orlonger if required by local requirements) of study therapy. The method ofcontraception must be a barrier method plus a hormonal method to preventpregnancy.

15. Participants must agree to continue contraception throughout the study andcontinuing through 3 months after the last dose of study drug. Note: If thechildbearing potential changes after start of the study (e.g., woman who is notheterosexually active becomes active, premenarchal woman experiences menarche)the woman must begin a highly effective method of birth control, as describedabove.

16. A woman of childbearing potential must have a negative serum or urine (b- humanchorionic gonadotropin [b-hCG]) at Screening.

17. A woman must agree not to donate eggs (ova, oocytes) for the purposes ofassisted reproduction during the study and for 6 months after receiving thelast dose of study drug.

18. A female participant must agree not to be pregnant, or breast-feeding, orplanning to become pregnant while enrolled in this study or within 3 monthsafter the last dose of study treatment.

19. A man who is sexually active with a woman of childbearing potential must agree touse a condom with spermicidal foam/gel/film/cream/suppository and his partner mustalso be practicing a highly effective method of contraception (i.e., established useof oral, injected or implanted hormonal methods of contraception; placement of anintrauterine device [IUD] or intrauterine system [IUS]). If the subject isvasectomized, he must still use a condom (with or without spermicide), but hisfemale partner is not required to use contraception. The subject must also notdonate sperm during the study and for 6 months after receiving the last dose ofstudy drug, even if he has undergone a successful vasectomy.

Exclusion Criteria:

1. Participant has received an investigational drug within a 28-day period (or within 5half-lives, whichever is shorter) before the first dose of study drug or iscurrently participating in another interventional clinical trial, unless in theopinion of the Sponsor-Investigator, the medication will not interfere with thestudy procedures or compromise subject safety.

2. The participant cannot have ever received an EGFR TKI (e.g. osimertinib), EGFR-directed monoclonal antibody (e.g. cetuximab), MET TKI (e.g. capmatinib, tepotinib),MET-directed monoclonal antibody (e.g. amivantamab) or MET-directed antibody-drugconjugate (e.g. telisotuzumab vedotin) prior to study entry. For patients with ALKor ROS1 NSCLC, crizotinib cannot be used within 3 months of screening.

3. Participants who have progressed on a TKI in less than 8 weeks

4. The participant has evidence of neuroendocrine differentiation or small celltransformation on the screening biopsy.

5. The patient has no evidence of an ALK, ROS1, and RET gene fusion as determined bymolecular testing. Acquired resistance mechanisms detected through NGS (or FISH)testing for which alternative therapies exist may potentially be eligible afterconsultation with the PI.

6. Participants with active, symptomatic, central nervous system disease defined asfollows:

7. Leptomeningeal disease.

8. Symptomatic cord compression from metastatic disease.

9. Untreated, symptomatic brain metastases

10. Patients with brain metastases may be potentially eligible provided that allthe following criteria are met: i. They are not on prednisolone 20mg equivalents daily prior to enrolling in thestudy. ii. Anticonvulsants will be permitted provided the patient has been on a stable dosefor a period of 2 weeks prior to Study Day 1. iii. Procedural interventions (such as ventriculoperitoneal shunt) greater than 12weeks prior to Study Day 1. iv. Palliative radiotherapy (either whole brain radiotherapy or stereotacticradiosurgery) ≥ 28 days prior to screening.

11. Participant has active cardiovascular disease defined as the following:

12. Congestive heart failure (CHF), defined as New York Heart Association (NYHA)class III-IV or hospitalization for CHF within 6 months of study Day 1.

13. Symptomatic acute coronary syndrome, unstable angina, or active ischemiarequiring coronary artery stenting, angioplasty, or bypass grafting within 12weeks prior to starting investigational drug.

14. Participant has evidence of current, uncontrolled, clinically significant,unstable arrhythmias. Participants receiving active anti-arrhythmic therapy arenot eligible with the following exceptions: i. Participants with atrial fibrillation medically controlled for greater than 4weeks prior to Study Day 1. ii. Participants who have medical pacemakers for control of arrhythmias. d.Participant has medically uncontrolled hypertension (defined as ≥ 160 mmHg systolicblood pressure (SBP) and ≥ 100 mmHg diastolic blood pressure (DBP). e. Clinically significant, acute deep vein thrombosis or pulmonary embolism within 6months prior to first dose of study drug. Clinically non-significant thrombosis,such as non-obstructive catheter-associated clots or incidentally detected,asymptomatic, subsegmental pulmonary emboli are not considered exclusionary. f. History of cerebrovascular accident or transient ischemic attack within12 weeksof enrollment. g. QT interval corrected by Fridericia's Formula (QTcF) prolongation to > 470msbased on a 12-lead electrocardiogram.

15. Participant has any history of interstitial lung disease (ILD), including druginduced ILD or radiation pneumonitis requiring treatment with prolonged steroids orother immune suppressive agents that is unresolved or resolved within the last 3months

16. Participant has clinical evidence or history of ongoing significant bowelobstruction limiting oral intake, active uncontrolled malabsorption syndromes, orany other gastrointestinal disorder or defect that would interfere with absorption,distribution, metabolism, or excretion of the study drug and/or predispose thesubject to an increased risk of gastrointestinal toxicity.

17. Participant has an additional primary malignancy within 2 years prior to enrollmentwith following exceptions:

18. Adequately resected non-melanoma skin cancer.

19. Superficial bladder tumors (Ta, Tis, or T1).

20. Adequately treated intraepithelial carcinoma of the cervix uteri.

21. Low-risk, non-metastatic prostate cancer following local treatment or ongoingactive surveillance.

22. Any other curatively treated in situ disease.

23. Participant is positive for human immunodeficiency virus (HIV), with 1 or more ofthe following: f. Receiving ART that may interfere with study treatment (consult sponsorinvestigator for review of medication prior to enrollment) g. CD4 count ≤ 350 atscreening h. AIDS-defining opportunistic infection within 6 months of the start ofscreening i. Not agreeing to start ART and be on ART > 4 weeks plus having HIV viralload < 400 copies/mL at the end of 4-week period (to ensure ART is tolerated and HIVcontrolled).

24. Participant has active/chronic, known, untreated, hepatitis B as demonstrated by apositive hepatitis B surface antigen (HBsAg). Note: Subjects with a prior history ofHBV demonstrated by positive hepatitis B core antibody are eligible if they have thefollowing at Screening: j. Negative HBsAg. k. HBV DNA (viral load) below the lower limit of quantification,per local testing. l. Subjects with a positive HBsAg due to recent vaccination are eligible if HBV DNA (viral load) is below the lower limit of quantification, per local testing.

25. Participant has active/chronic, known, untreated, hepatitis C infection asdemonstrated by a positive HCV antibody with detectable HCV viral load. Note: Subjects with a prior history of HCV, who have completed antiviral treatmentand have subsequently documented HCV RNA below the lower limit of quantification perlocal testing are eligible.

26. Participant has a concurrent and uncontrolled medical illness which would precludestudy conduct and assessment, including, but not limited to the following medicalconditions: an active infection requiring systemic therapy, bleeding disorder,clinically unstable ophthalmologic condition, diabetes mellitus with end-organdamage, pulmonary diseases, or alcoholic liver disease.

27. Participant is a pregnant or lactating woman.

28. Participant has a history of severe allergic reactions to any of the studyintervention components.

29. Participant has a medical or psychiatric condition, which might compromise theirability to give written informed consent or to comply with the study protocol visitsand procedures.

30. Participant has immune-mediated rash from checkpoint inhibitors that has notresolved prior to enrollment.

31. Use of live or live-attenuated vaccines within 30 days of screening.

32. Participant has significant reversible toxicities from prior anti-cancer therapythat have not recovered to Grade 1 or baseline (higher grades of alopecia andneuropathy up to Grade 2 will be permitted).

33. Participant had major surgery excluding placement of vascular access or tumorbiopsy, or had significant traumatic injury within 4 weeks before enrollment, orwill not have fully recovered from surgery, or has surgery planned during the timethe participant is expected to participate in the study. Note: Participants withplanned surgical procedures to be conducted under local anesthesia may participate.